The main psychoactive component of marijuana is known as delta9-tetrahydrocannabinol (THC). In addition, it has recently been discovered that endogenous substances are synthesized in the brain that can activate cannabinoid receptors, and these substances are referred to as endocannabinoids. All drugs, both natural and synthetic, that act at receptors for this substance are known collectively as cannabinoids (CBs). Cannabinoid drugs obtained by the smoking or ingestion of marijuana are used illicitly presumably because they are reinforcing or rewarding to humans. One of the objectives of these studies is to gain knowledge about the underlying mechanisms through which cannabinoids alter brain cell function, and ultimately the mechanisms that produce the pleasurable effects of these drugs that sustain their illicit use. The primary focus of this laboratory is to examine the mechanisms through which abused drugs alter the electrical activity of neurons and the ways in which these neurons communicate with each other via synaptic connections. Therefore, one of our goals is to identify specific ion channels whose activity is modified by abused drugs such as marijuana, nicotine, heroin, and cocaine. To achieve these goals we will utilize rat brain slices acutely obtained from discrete brain areas involved in processing information regarding pleasurable and unpleasant environmental stimuli. We utilize whole-cell electrophysiological recordings, and cellular anatomical techniques to reconstruct the neurons from which we record. In these ongoing studies we are examining the mechanisms through which these drugs affect neurons and their connections in the ventral tegmental area (VTA). This brain area and its connections are strongly implicated in the reinforcing and rewarding actions of all abused drugs, as well as in mediating the rewarding effects of natural environmental stimuli, such as food, water, etc. The VTA is also involved in processing information regarding the physiological stress responses, mood and affect, and mental alertness. Because of its central role in these processes, the VTA is a brain area that contributes to disorders such as addiction, psychiatric stress disorders, clinical depression, and psychiatric anxiety disorders. Recent studies in the laboratory have focused on delineating the relative contribution of synaptic inputs to the VTA dopamine neurons arising from distinct brain regions. One of the sub-cortical inputs to the VTA that we are currently studying is that from the pedunculopontine nucleus (PPN). This brain nucleus provides strong acetylcholinergic (Ach) input to the VTA, and therefore is likely involved in regulating the reinforcing and addictive properties of the drug nicotine. Therefore, these studies will provide information that will be useful in the treatment of nicotine addiction, as well as in the prevention of respiratory disorders, such as emphysema, and lung cancer, resulting from nicotine addiction. Moreover, since the PPN is known to be critical to setting states of alertness, and physiological arousal, it is strongly implicated as a subcortical brain structure involved in anxiety, and chronic stress disorders. Our most recent studies examine the properties of the PPN input to the VTA, with regard to nicotine sensitivity, as well as the ability of this pathway to undergo a long-term change know as long-term depression (LTD) following exposure to either environmental stress or cocaine. We have found that the PPN inputs to the VTA can be weakened if animals are exposed to stress, or cocaine, and that nicotine exposure can alter the ability of the PPN to activate the reward-relevant dopamine neurons in the VTA. In order to further these studies we have also developed a genetically altered mouse in which the green fluorescent protein (GFP) is expressed only in dopamine neurons. The use of confocal microscopy in brain slices containing the VTA permits us to identify these neurons prior to performing electrophysiological studies. This has greatly increased the speed of data collection in the laboratory.